Throughout this application various publications are referenced to by arabic numerals within parenthesis. Full bibliographic citations for these references may be found at the end of the specification immediately preceding the claims. The disclosures for these publications are hereby incorporated by reference into this application to more fully describe the state of the art to which this invention pertains.
One of the active compounds of this invention have been known to the art for some time. Gossypol has the structure: ##STR1## and is known as a yellow pigment obtained from the cotton plant. Primarily, it has been noted as a potential antifertility agent, see e.g., National Coordinating Group on Male Antifertility Agents - cotton phenol (gossypol) in Clin. Med. J. 8:455-458 (1980); and Gynecol. Obstet. Invest. 10:163-176 (1979). It has been observed as well, that gossypol is selectively toxic to testicular tissues, with no observable effect on other tissues (55, 56, 57). The mechanism of the drug's contraceptive action, its pharmokinetics, and the basis for its toxicological action are not understood.
Recently, cell culture studies have shown that gossypol has anti-tumor effects against cultured tumor cell lines (58, 59, 60, 61). One factor common to tumor cells which were found sensitive to the drug was a high level of lactate dehydrogenase, especially cathodic forms of this enzyme (59). Biochemical studies of gossypol have shown that the principle action of the drug is in inhibition of glycolytic and mitochondrial bound enzymes, with interference of ion transport (58, 62-71).
Rhodamine 123 is a cationic fluorescent dye which binds specifically to mitochondria of living cells (72, 73), and it has been used as a supravital mitochondrial probe for long term cell culture studies. Continuous exposure of cells to rhodamine 123 at high doses, is found to inhibit oxidative phosphorylation, to arrest cells in G.sub.1 phase, and to induce loss of reproductive capacity (72, 73, 74). Some further studies of the toxic effect of rhodamine 123 on a variety of cell lines in culture have led to the tentative conclusion that the dye may be selectively cytotoxic against carcinoma cells, probably because of prolonged retention in carcinoma mitochondria (75).
Hyperthermia, or heat treatment of cancer cells, has been a recognized form of cancer therapy for sometime. Briefly, in hyperthermic treatment, cancer cells are treated, locally, with temperatures as high as 42.degree. C. This localized heat treatment is observed to inhibit or to destroy cancer cells with no appreciable harm to normal cells. Systemic hyperthermia, or application of heat to raise the temperature of the body is also used. In this case, care must be taken so that the temperature is not raised above the temperature where normal tissue is destroyed.
Anti-fertility drugs have recently received attention as being useful as hyperthermic sensitizers, i.e., when applied to cancer cells, the compounds tend to increase the efficacy of the heat treatment (24, 76, 77). No work has been done, however, on the effect of gossypol, or rhodamine 123, in the context of hyperthermic sensitivity.
However, in some situations, such as when heating the tumor mass to greater than 42.degree. C. is not feasible because the tumor being treated is deep seated and/or cooled by close opposition to large normal blood vessels, trimodality therapy is able to control tumor masses. For the purposes of this invention, trimodality therapy is defined as therapy encompassing the use of a compound, radiation and heat.